4-allyloxy-3-chloro-phenyl-acetic acid

ABSTRACT

ACIDS OF THE FORMULA   1-(R1O-),2-R2,4-(HOOC-CH(-R4)-),6-R3-BENZENE   WHEREIN: R1 REPRESENTS A LINEAR OR BRANCHED ALKYL RADICAL C2-C8; A LINEAR OR BRANCHED ALKENYL RADICAL C2-C4; AN ALKNYL RADICAL; C3-C4; A CYCLOALKENYL RADICAL C5-C6; A BENZYL RADICAL; OR A BENZYL RADICAL SUBSTITUTED BY AN ALKYL RADICAL, AN ALKOXY RADICAL OR A HALOGEN; R2 AND R3 EACH REPRESENT A LINEAR OR BRANCHED ALKYL RADICAL C1-C3, A LOWER ALKENYL RADICAL C2-C4, A LOWER ALKOXY RADICAL C1-C4 OR A HALOGEN ATOM, R2 AND R3 BE ING INDENTICCAL OR DIFFERENT, ONE OF SAID R2 AND R3 MAY ALSO BE HYDROGEN; R4 REPRESENTS HYDROGEN OR A LINEAR OR BARANCHED LOWER ALKYL RADICAL C1-C4, SALTS THEREOF; PREPARATION OF THE ABOVE, AND THEIR USE AS ANTIPYRETIC, ANTI-INFLAMMATORY, ANALGASIC AND ANTISPASMODIC AGENTS.

u y 1974 NGUYEN PHUC BUU-HOI ETAL 3,824,277

*ALLYLOXY-S-CHLORO-PHEHYL-ACETIC ACID Filed May 26, 1970 2 Sheets-Sheet 1 0 Pain relief score Patient '6 (:SUOmgmral) 20 .MCMERVAN ptasmatic levels(mcg,ml

F|G-1. Relationships between "CWIervan plasmatic concentrations and analgesic activity.

July 16, 1974 Filed llay 26, 1970 Decrease in Temperature (C) NGUYEN PHUC BUU-HOI E AL 3,824,277

4-ALLYLOXY-B-CHLORO-PHENYL-ACETIC ACID 2 Sheets-Shoat 3 Acetyloalicyllic acid 5 administered orally.

- Dosage1250 mg/kg Mervah adm'nhistered orally- Dosage: ZOOrng/kg Mervan administered subcutaneously. Dosage: mg/kg Time (mins) United States Patent US. Cl. 260-521 A 1 Claim ABSTRACT OF THE DISCLOSURE Acids of the formula wherein R represents a linear or branched alkyl radical C -C a linear or branched alkenyl radical C C an alkynyl radical C -C a cycloalkenyl radical C -C a benzyl radical; or a benzyl radical substituted by an alkyl radical, an alkoxy radical or a halogen;

R and R each represent a linear or branched alkyl radical C 0 a lower alkenyl radical C -C a lower alkoxy radical C -C or a halogen atom, R and R, being identical or different, one of said R and R may also be hydrogen;

R represents hydrogen or a linear or branched lower alkyl radical C -C salts thereof; preparation of the above, and their use as antipyretic, anti-inflammatory, analgesic and antispasmodic agents.

formula I.

I R1O@(IJHC 0 OH I R4 R: (I) wherein:

R represents a linear or branched alkyl radical C -C a linear or branched alkenyl radical C -C an alkynyl radical C C a cycloalkenyl radical C -C a benzyl radical; or a benzyl radical substituted by an alkyl radical C -C an alkoxy radical C -C or a halogen;

R and R each represent a linear or branched alkyl radical C -C a lower alkenyl radical C C a lower alkoxy radical C -C or a halogen atom, R and R be ing identical or different, one of said R and R may also be hydrogen;

R represents hydrogen or a linear or branched lower alkyl radical C -C 3,824,277 Patented July 16, 1974 This invention also relates to salts of alkaline and alkaline-earth metals and to amine salts of said acids.

The inventors have found that said compounds have numerous applications in pharmaceutical field due to their antipyretic, anti-inflammatory, analgesic and antispasmodic activity. The toxicity of said compounds is very low. The following derivatives are some examples of active products having general formula (I).

3-chloro=4-allyloxyphenylacetic acid 3-chloro-4-propargyloxyphenylacetic acid 3-chloro-4-crotyloxyphenylacetic acid 3-chloro-4-isopropyloxyphenylacetic acid 3-chloro-4-metallyloxyphenylacetic acid 3-chloro-4-narnyloxyphenylacetic acid 3-methoxy-4-allyloxyphenylacetic acid 3-1nethoxy-'4-n-propyloxyphenylacetic acid 3-methoxy-4-metallyloxyphenylacetic acid 3-methoXy-4-crotyloxyphenylacetic acid 3-methoxy-4-propargyloxyphenylace'tic acid 3methyl-4-allyloxyphenylaceic acid 3-methyl-4-propargyloxyphenylacetic acid 3-rnethyl-4-rnetallyloxyphenylacetic acid 3-methyl-4-crotyloxyphenylacetic acid 3-methyl-4-n-butyloxyphenylacetic acid 3'bromo-4-allyloxyphenylacetic acid 3 fluoro-4-ally1oxyphenylacetic acid 3-bromo-4-pr0pargyloxyphenylace'tic acid 3-fiuoro-4-propargyloxyphenylacetic acid 3-bromo-4-n-butyloxyphenylacetic acid 3-fluoro-4-crotyloxyphenylacetic acid '3-fiuoro4-n-butyloxyphenylacetic acid 3-ethy1-4-allyloxyphenylacetic acid 3-ethy1-4-n-propyloxyphenylacetic acid 3-isopropyl-4-n-butyloxyphenylacetic acid 3-isopropyll-allyloxyphenylacetic acid 3-ethoxy-4-propargyloxyphenylacetic acid 3-ethoxy-4-allyloxyphenylacetic acidl B-ethoXy-4-n-propyloxyphenylacetic acid 3.5-dibromo-4-allyloxyphenylacetic acid 3.5-dichloro-4-allyloxyphenylacetic acid 3.5-dibrorno-4-propargyloxyphenylacetic acid 3.5-dimethyl-4-allyloxyphenylacetic acid 3.5-dimethyl-4-n-propyloxyphenylacetic acid 3.5-dimethyl-4-propargyloxyphenylacetic acid 3 .5-dichloro-4-propargyloxyphenylacetic acid 3.5-dichloro-4-n-propyloxyphenylacetic acid 3-chloro-5-methyl-4-allyloxyphenylacetic acid 3-chloro-5-methyl-4-n-propyloxyphenylacetic acid 3-chloro-5-methoxy-4-allyloxyphenylacetic acid 4-isobutyloxy-3.S-dichlorophenylacetic acid 4-n-butyloxy-3 .S-dichlorophenylacetic acid 4-sec butyloxy-3.S-dichlorophenylacetic acid 4-amyloxy-3.S-dichlorophenylacetic acid 4-isoamyloxy-3,5-dichlorophenylacetic acid 3.5-dichloro-4-iso propyloxyphenylacetic acid a (3-chloro-4-allyloxyphenyl)propionic acid at 3-bromo-4-allyloxypheny1)propionic acid on (3-br0mo-4-propargyloxyphenyl)propionic acid a (3- fiuoro-4-allyloxyphenyl)propionic acid a (3-chloro-4-n-propyloxyphenyl)propionic acid a (3-chloro-4-propargyloxyphenyl)propionic acid a (4-allyl0xy-3.S-dichlorophenyl)propionic acid on (3.S-dichloro-4-propargyloxyphenyl)propionic acid a (3.5-dichloro-4-propyloxyphenyl)propionic acid a (4-isobutyloxy-3.S-dichlorophenyll propionic acid a (3-chloro-4-isopropyloxyphenyl)propionic acid a (4-allyloxy-3-fiuorophenyl)propionic acid on (3-fluoro-4-isopropyloxyphenyl)propionic acid a (3-fluoro-4-propargyloxyphenyl)propionic acid a (4-allyloxy-3-chlorophenyl)butyric acid a (3-chloro-4-propargyloxyphenyl)butyric acid 3bromo-5-chloro4-allyloxyphenylacetic acid 3methoxy-5bromo4-allyloxyphenylacetic acid 3bromo-5-methyl'4-allyloxyphenylacetic acid 3bromo-S-methyl-4-propargyloxyphenylacetic acid 3bromo-S-methyl-4-crotyloxyphenylacetic acid 3-chloro-4-(AZ-cyclohexenyloxy)phenylacetic acid 3-chloro-4-(AZ-cyclopentenyloxy)phenylacetic acid 3-methyl-4- (AZ-cyclohexenyloxy)phenylacetic acid 3-methoxy-4-(AZ-cyclohexenyloxy)phenylacetic acid.

Examples of salts of acids of formula I which are useful according to the invention are:

Sodium 3chloro4-allyloxyphenylacetate Magnesium 3-chloro-4-allyloxyphenylacetate Ethanolamine 3-chloro4-allyloxyphenylacetate Ethanolamine 3fluoro-4-propargyloxyphenylacetate Ethanolamine 3fluoro-4-allyloxyphenylacetate Butylamine 3chloro-4-allyloxyphenylacetate.

The general process for preparing acids of formula I comprises hydrolysing a compound of formula 11:

R10 CH-X a 4 (11) wherein R R R and R have the meaning given hereinbefore and X represents the nitrile function CN or the ester function COOR in which R represents a lower alkyl radical.

When X represents the nitrile function CN in formula II, hydrolysis is carried out in acid or basic medium so as to obtain the acid involved.

When X represents the ester function COOR in formula II, said ester is obtained by starting from an ester of a substituted p-hydroxyphenylacetic acid of the formula III wherein R R R and R have the meaning given hereinabove, this ester being alkylated in position para with an alkyl, alkenyl, alkynyl or cycloalkenyl halide, then the ester so obtained is hydrolysed in order to obtain the acid desired.

Several examples of preparation of substituted acids and salts thereof according to the invention are given hereinafter, said examples being not intended to restrict the scope of the invention.

EXAMPLE 1 3-chloro4-crotyloxyphenylacetic acid 100 g. of methyl 3-chloro-4-hydroxyphenylacetate (0.5 mol), 67.5 g. of crotyl bromide (0.5 mol), 69 g. of anhydrous potassium carbonate and 150 cc. of acetone are refluxed for 6 hours with vigorous stirring. After cooling, the mixture is diluted with water and extracted with ether. The ethereal phase is washed With Water, carbonate and water, dried on magnesium sulfate and evaporated. The distillation of the residue gives 91.4 g. of methyl 3-ch1oro 4-crotyloxyphenylacetate. Boiling point: 1 60164 C./2 mm.; n 1.5300; yield: 72%.

50.8' g. of methyl 3chloro4-crotyloxyphenylacetate (0.2 mol), 22 g. of potassium hydroxide, 50 cc, of water and 150 cc. of methanol are refluxed for 2 hours. The methanol is evaporated, the residue is diluted with water and ice and acidified with 20% HCl. The solid is filtered, washed with petroleum ether and dried. The crude product, 39.8 g. (83%), is recrystallised from a mixture of benzene/petroleum ether. Melting point: 82-83 C. (benzene-petroleum ether).

Analysis.--Calculated (percent): C, 59.88; H, 5.44. Found (percent): C, 59.75; H, 5.26.

4 EXAMPLE 2 3methoxy-4-allyloxyphenylacetic acid 10 g. of methyl 3methoxy-4-hydroxyphenylacetate (0.051 mol), 7 g. of anhydrous potassium carbonate, 6.2 g. of allyl bromide and 20 cc. of acetone are refluxed for 6 hours with vigorous stirring. The mixture is diluted With water, extracted with ether, the ethereal phase is washed with water, carbonate and water, then dried on sodium sulfate and evaporated. The residue rectified under vacuum gives 9.4 g. of methyl 3methoxy-4-allyloxyphenylacetate having a boiling point of 160161 C./2.5 mm.; n 1.5264; yield: 78%.

4.7 g. of methyl 3methoxy-4allyloxyphenylacetate, 62 g. of potassium hydroxide, 20 cc. of methanol and 5 cc. of Water are refluxed for 2 hours. Maximum alcohol is evaporated, the residue is diluted with Water and ice, the product is acidified with 20% HCl and the solid is filtered. 3.3 g. of 3methoxy-4-allyloxyphenylacetic acid are obtained with a melting point of B l-82 C. (petroleum etherbenzene); yield: 77%.

Analysis.Calculated (percent): C, 64.85; H, 6.35. Found (percent): C, 64.62; H, 6.24.

EXAMPLE 3 3 methyl-4-allyloxyphenylacetic acid 45 g. of methyl 3-methyl-4-hydroxyphenylacetate (0.25 mol), 34.5 g. of potassium carbonate, 30.5 g. of allyl bromide and cc. of acetone are refluxed for 6 hours with vigorous stirring. The mixture is diluted with Water and extracted with ether. The ethereal phase is washed with water, bicarbonate and water, then dried on magnesium sulfate, the solvent is evaporated and the residue is rectified under vacuum. 43 g. of methyl 3-methy1-4-allyloxyphenylacetate are obtained. Boiling point: 138-140 C./1.5 mm.; 11 1.5157; yield: 78.2%.

11 g. of methyl 3methyl-4-allyloxyphenylacetate (0.05 mol); 2.8 g. of potassium hydroxide, 2.5 cc. of Water and 25 cc. of methanol are refluxed for 2 hours. Maximum alcohol is evaporated, the residue is diluted with water and ice, then acidified with 20% HCl and the solid is filtered. 10.5 g. of a crude product are obtained, which after having been twice recrystallised from a mixture of benzene and petroleum ether gives 6.5 g. of 3-methyl-4-allyloxyphenylacetic acid. Yield: 63.1%; melting point: 65 -67 C. (petroleum ether-benzene).

Analysis.Calculated (percent): C, 69.88; H, 6.84. Found (percent): C, 69.68; H, 6.85.

EXAMPLE 4 3chloro-4allyloxyphenylacetic acid 23 g. of ethyl 3-chloro4-hydroxyphenylacetate, 16.2 g. of potassium carbonate, 14.5 g. of allyl bromide and 50 cc. of anhydrous acetate are refluxed for 6 hours with stirring.

The mixture is cooled, diluted With Water and extracted with ether. The ethereal phase is Washed with 10% carbonate and water, dried on magnesium sulfate and evaporated, The residue rectified under vacuum gives 22.6 g. of ester. Yield: 81.6%; boiling point: -122 C./0.2 mm.; 11 1.5331.

22 g. of methyl 4-allyloxy-3-chlorophenylacetate and 50 cc. of 20% sodium hydroxide are refluxed for 1 hour. The solution is cooled and washed with ether, then acidified with 20% HCl and the precipitate is Washed with Water. A recrystallisation from cyclohexane gives 16.1 g. of product. Yield: 78%; melting point: 9192 C.

Analysis.Calculated (percent): C, 58.29; H, 4.89; Cl, 15.64. Found (percent): C, 58.32; H, 4.71; C1, 15.51.

EXAMPLE 5 3-fiuoro-4-propargyloxyphenylacetio acid 40 g. of methyl 3fluoro4-hydroxyphenylacetate, 31 g. of anhydrous potassium carbonate, 26.5 g. of propargyl bromide and 100 cc. of anhydrous acetone are mixed. The mixture is refluxed for 6 hours with stirring. The mixture is cooled, diluted with water and extracted with ether. The ethereal phase is Washed with carbonate, then with water, dried on magnesium sulfate and evaporated. The residue rectified under vacuum gives 43.9 g. of ester. Yield: 94%; B.P.: 140-142 C. (1 mm.); n 1.5130.

22.2 g. of methyl 3-fiuoro-4-propargyloxyphenylacetate (0.1 mol), 10 g. of potassium'hydroxide, 20 cc. of water and 100 cc. of methanol are refluxed for 2 hours. The alcohol is distilled out and the residue is diluted with water. The aqueous phase is Washed with ether and acidified with 20% hydrochloric acid. The precipitate is filtered, washed with water and recrystallised from a mixture of cyclohexane-benzene. M.P.: 93-95 C.

Analysis.--Calculated (percent): C, 63.46; H, 4.36. Found (percent): C, 63.52; H, 4.18.

EXAMPLE 6 4croty1oxy-3 ethoxyphenyl:acetic acid 47 g. of methyl 3-ethoxy-4-hydroxyphenylacetate, 31 g. of anhydrous potassium carbonate, 33 g. of crotyl bromide and 100 cc. of anhydrous acetone are refluxed with stirring for 6 hours. The mixture is cooled, diluted with water and extracted with ether. The ethereal phase is washed with 10% carbonate, then with water, dried on magnesium sulfate and evaporated. The residue rectified under vacuum gives 44 g. of ester. Yield: 74%; B.P.: 140- 144 C. (1 mm); n 1.5210.

g. of methyl 4-crotyloxy-3-ethoxyphenylacetate, 10 g. of sodium hydroxide, cc. of water and 100 cc. of methanol are-refluxed for 2 hours. The alcohol is distilled out and the residue is diluted with water. The aqueous phase is washed with ether, then acidified with 20% hydrochloric acid. The precipitate is filtered, washed with water and recrystallised from cyclohexane. M.P.: 7577 C.; yield 73%.

Analysis-Calculated (percent): C, 67.18; H, 7.25. Found (percent): C, 67.21; H, 717.

EXAMPLE 7 4-crotyloxy-3-methylpheny1acetic acid 17 g. of methyl 4-hydroxy-3-methylphenyl-acetate, 13.2 g. of anhydrous potassium carbonate, 12.9 g. of crotyl bromide and 50 cc. of acetone are refluxed with stirring for 6 hours. The mixture is cooled, diluted with water and extracted with ether. The ethereal phase is washed with 10% carbonate, then with water, dried on magnesium sulfate and evaporated. The residue rectified under vacuum gives 19.4 g. of ester. Yield: 87.4%; B.P.: 137- 139 C./1 mm.; n 1.5386.

9.5 g. of this ester and 50 cc. of a 20% aqueous sodium hydroxide solution are stirred at room temperature for 2 hours. The mixture is washed with ether and acidified with 20% HCl. The precipitate is filtered, washed with water and recrystallised from petroleum ether; M.P.: 8687.5 C.

Analysis-Calculated (percent): C, 70.88; H, 7.32. Found (percent): C, 70.52; H, 7.28.

EXAMPLE 8v 3-bromo-5-methyl-4-propargyloxyphenylacetic acid 52 g. of methyl 3-bromo-4-hydroxy-5-methylpheny1- acetate, 27.2 g. of potassium carbonate, 24 g. of propargyl bromide and 60 cc. of acetone are refluxed for 6 hours with stirring. After cooling, the mixture is diluted with water and extracted with ether. The ethereal phase is washed with 10% carbonate, then with water, dried on magnesium sulfate and evaporated. The residue rectified under vacuum gives 48.5 g. of ester. Yield: 81%; B.P.: 150 C./0.8 rnm.. n 1.5452.

25 g. of methyl 3-bromo- 5-methyl-4-propargyloxyphenylacetate, 6 g. of KOH, 10 cc. of water and 100 cc. of

methanol are refluxed for 4 hours. The mixture is cooled and washed with ether. The aqueous phase is acidified with 20% HCl. The precipitate is filtered, washed with water and recrystallized from ether-petroleum ether. There is obtained 13.5 g. of product having a melting point of 151153 C.; yield 60%.

Analysis.Calcu1ated (percent): C, 50.90; H, 3.91. Found (percent): C, 50.89; H, 3.92.

EXAMPLE 9 '4-allyloxy-3,S-dichlorophenylacetic acid 56 g. of methyl 3.5-dichloro-4-hydroxyphenylacetate, 32 g. of anhydrous potassium carbonate, 20 cc. of allyl bromide and cc. of anhydrous acetone are refluxed for 6 hours with stirring. After cooling, the mixture is diluted with water and extracted with ether. The ethereal phase is washed with 10% carbonate, then with water, dried and evaporated. The residue rectified under vacuum gives 43.5 g. of ester; yield: 70%; B.P.: 146-148 C./ 1 mm.; n 1.538.

20 g. of methyl 4-allyloxy-3.S-dichlorophenylacetate and 50 cc. of 20% sodium hydroxide are stirred for 2 hours at room temperature. The solution is washed with ether and acidified with 20% HCl. The precipitate is filtered, washed with water and recrystallised from cyclohexane. There are obtained 15.1 g. of product. Yield: 82%; M.P.: 118-119 C.

Analysis.-Calculated (percent): C, 50.60; H, 3.86. Found (percent): C, 50.76; H, 3.80.

EXAMPLE 1'0 3-ethyl-4-propargyloxyphenylacetic acid 43 g. of methyl 3-ethyl-4-hydroxyphenylacetate, 30.5 g. of anhydrous potassium carbonate, 29 g. of propargyl bromide and 60 cc. of acetone are refluxed for 6 hours with stirring. After cooling, the mixture is diluted with water and extracted with ether. The ethereal phase is washed with 10% carbonate, then with water, dried on magnesium sulfate and evaporated. The residue rectified under vacuum gives 38.6 g. of ester; yield: 75.9%; B.P.: 124-127" C./0.5 mm.; n 1.5238.

38 g. of methyl 3-ethyl-4-propargyloxyphenylacetate and 100 cc. of 20% sodium hydroxide are stirred for 2 hours at room temperature. The mixture is washed with ether and acidified with 20% HCl. The precipitate is filtered, washed with water, dried and recrystallised from cy-clohexane. There are obtained 22.3 g. of acid; yield: 60%; M.P.: 81.5-83 C.

Analysis.Calculated (percent); C, 71.54; H, 6.47. Found (percent): C, 71.48; H, 6.38.

EXAMPLE 11 4-allyloxy-2-chloro-5-methoxyphenylacetic acid 74 g. of methyl 3-chloro-4-hydroxy-S-methoxyphenylacetate, 44 g. of anhydrous potassium carbonate, 46 g. of allyl bromide and cc. of acetone are refluxed for 6 hours with stirring. After cooling, the mixture is diluted with water and extracted with ether. The ethereal phase is washed with 10% carbonate, then with water, dried on magnesium sulfate and evaporated. The residue rectified under vacuum gives 43 g. of ester. Yield: 50%; B.P.: 157-162 C./3 mm.; n 1.5291.

21 g. of this ester and 100 cc. of a 20% aqueous sodium hydroxide solution are stirred for 2 hours at room temperature. The mixture is washed with ether and acidified with 20% -HCl. The precipitate is filtered, washed with water and recrystallised from benzene-petroleum ether. There are obtained 15 g. of acid. Yield: 72%; M.P.: 123.5-125.5 C.

Analysis-Calculated (percent): C, 56.15; H, 5.10. Found (percent): C, 56.05; H, 5.21..

7 EXAMPLE 12 4-allyloxy-3.5-climethylphenylacetic acid 46.8 g. of methyl 3.5-dimethyl-4-hydroxyphenylacetate, 27 g. of anhydrous potassium carbonate, 25 g. of allyl bromide and 100 cc. of dry acetone are refluxed with stirring. After cooling, the mixture is diluted with water and extracted with ether. The ethereal phase is washed with carbonate, then with water, dried on magnesium sulfate and evaporated. The residue rectified under vacuum gives 32 g. of ester. Yield: 70%; B.P.: 146 C./2 mm.; n 1.50.

16 g. of this ester and 50 cc. of a aqueous sodium hydroxide solution are stirred for 2 hours at room temperature. The mixture is Washed with eter, acidified with 20% HCl, the precipitate is filtered and recrystallised from aqueous methanol. There are obtained 9.9 g. of acid. Yield: 70%; M.P.: 88-99 C.

A|nalysis.--Calculated (percent): C, 70.89; H, 7.32. Found (percent): C, 71.07. H, 7.30.

EXAMPLE 13 a-(4-allyloxy-3-chlorophenyl)propionic acid 21.4 g. of methyl a-( 3 chloro-4-hydroxyphenyl)propionate, 13.8 g. of anhydrous potassium carbonate, 12.5 g. of allyl bromide and 50 cc. of acetone are refluxed for 6 hours with stirring. The mixture is cooled, diluted with water and extracted with ether. The ethereal phase is Washed with 10% carbonate, then with water, dried on magnesium sulfate and evaporated. The residue reetified under vacuum gives 19.4 g. (76%) of ester; B.P.: 170173 C./3 mm.; 11 1.5297.

10 g. of this ester and 50 cc. of a 20% aqueous sodium hydroxide solution are stirred for 2 hours at room temperature. The mixture is washed with ether and acidified with 20% HCl, then the precipitate is filtered and Washed with water. One recrystallises from ether-petroleum ether;

ANALYSIS M.P.: 3841 C.

Calculated (percent): C, 59.88; H, 5.44. Found (percent): C, 59.76; H, 5.32. In the same way, the following acids were prepared.

3-methoxy-4-proparglyoxyphenylacetic acid M.P.: 108.5 109 C. (benzene-petroleum ether): Calculated (percent): C, 65.44; H, 5.49. Found (percent): C, 65.16; H, 5.42.

3-methoxy-4-n-propyloxyphenylacetic acid M.P.: 72-74" C. (cyclohexane):

Calculated (percent): C, 64.27; H, 7.19. Found (percent): C, 64.18; H, 7.30.

4-allyloxy-3-ethoxyphenylacetic acid M.P.: 5960.5 C. (cyclohexane):

Calculated (percent): C, 66.09; H, 6.82. Found (percent): C, 66.28; H, 6.69.

3-ethoxy-4-propargyloxyphenylacetic acid M.P.: 9698 C. (benzene-petroleum ether):

Calculated (percent): C, 66.05; H, 6.02. Found (percent): C, 66.25; H, 5.99.

3-ethoxy-4-n-propyloxyphenylacetic acid M.P.: 72-73 C. (cyclohexane):

Calculated (percent): C, 65.53; H, 7.61. Found (percent): C, 65.23; H, 7.45.

4-allyloxy-3-bromo-5-methylphenylacetic acid M.P.: 1l8-119 C. (methanol-water):

Calculated (percent): C, 50.54; H, 4.60. Found (percent): C, 50.53; H, 4.61.

3-bromo-4-metallyloxy-S-methylphenylacetic acid M.P.: 109110 C. (cyclohexane):

Calculated (percent): C, 52.19; H, 5.05. Found (percent): C, 51.96; H, 5.01.

4-allyloxy-3-chloro-S-methylphenylacetic acid M.P.: 111.5112.5 C. (methanol-water): Calculated (percent): 59.88; H, 5.44. Found (percent): C, 59.60; H, 5.38.

3.5-dichloro-4-propargyloxyphenylacetic acid M.P.: l56159 C. (ethanol-Water):

Calculated (percent): C, 50.99; H, 3.11. Found (percent): C, 51.02; H, 3.07.

3.5-dichloro-4-n-propyloxyphenylacetic acid M.P.: 89-91 C. (petroleum ether):

Calculated (percent): C, 50.21; H, 4.60. Found (percent): C, 50.27; H, 4.57.

4-allyloxy-3.S-dimethylphenylacetic acid M.P.: 88-89 C. (methanol-water):

Calculated (percent): C, 70.89; H, 7.32. Found (percent): C, 71.07; H, 7.30.

3.5-dimethyl-4-propargyloxyphenylacetic acid M.P.: 122-123 C. (methanol-water):

Calculated (percent): C, 71.54; H, 6.47. Found (percent): C, 71.48; H, 6.36.

3.S-dimethyl-4-n-propyloxyphenylacetic acid M.P.: 66.5-68 C. (ethanol-water):

Calculated (percent): C, 70.24; H, 8.16. Found (percent): C, 70.32; H, 8.08.

4-crotyloxy-3.S-dimethylphenylacetic acid M.P.: 8384.5 C. (ethanol-water):

Calculated (percent): C, 71.77; H, 7.74. Found (percent): C, 71.85; H, 7.73.

3-bromo-4-n-butyloxyphenylacetic acid M.P.: 84-86 C. (methanol-Water):

Calculated (percent): C, 50.19; H, 5.26. Found (percent): C, 50.02; H, 5.15.

4-n-butyloxy-3-isopropylphenylacetic acid M.P.: 129-131 C. (methanol-Water):

Calculated (percent): C, 71.97; H, 8.86. Found (percent): C, 71.96; H, 8.68.

4-allyloxy-3-isopropylphenylacetic acid M.P.: 51-53 C. (acetic acid-water):

Calculated (percent): C, 71.77; H, 7.74. Found (percent): C, 71.80; H, 7.68.

4-allyloxy-3-ethylphenylacetic acid M.P.: 8l-83 C. (petroleum ether):

Calculated (percent): C, 59.39; H, 6.23. Found (percent): C, 59.48; H, 6.27.

The following compounds were also prepared accordto the present invention:

3-bromo-5-chloro-4-propargyloxyphenylacetic acid M.P.: 161162 C. (cyclohexane):

Calculated (percent): C, 43.53; H, 2.66. Found (percent): C, 43.68; H, 2.64.

M.P.: 124-125 C. (benzene-cyclohexane):

Calculated (percent): C, 57.90; H, 3.89. Found (percent): C, 57.85; H, 3.80.

M.P.: 7071 C. (pentane):

Calculated (percent): C, 52.00; H, 5.10. Found (percent): C, 52.25; H, 5.15.

4-n butyloXy-3,S-dichlorophenylacetic acid M.P.: 76-77 C. (hexane-acetone):

Calculated (percent): C, 52.00; H, 5.10.

Found (percent): C, 51.80; H, 5.05.

3-chloro-4-(p-methylbenzyloxy) phenylacetic acid M.P.: 127-128 C. (benzene-cyclohexane):

Calculated (percent): C, 66.09; H, 5.20.

Found (percent): C, 66.05; H, 5.10.

3-chloro-4-(2',4-dichlorobenzyloxy) phenylacetic acid M.P.: 175.5176 C. (benzene-cyclohexane):

Calculated, (percent): C, 52.13; H, 3.21.

Found (percent): C, 52.05; H, 3.00.

4-isoamyloxy-3-ethylphenylacetic acid M.P.: 3839 C. (methanol-Water):

Calculated (percent): C, 71.96; H, 8.85.

Found (percent): C, 71.95; H, 8.75.

3-ethyl-4-n octyloxyphenylacetic acid M.P.: 3738 C. (methanol-water):

Calculated (percent) C, 73.93; H, 9.65.

Found (percent) C, 73.78; H, 9.45.

4-is0 butyloXy-3,S-dichlorophenylacetic acid M.P.: 99100 C. (hexane):

Calculated (percent): C, 52.00; H, 5.10.

Found (percent): C, 51.85; H, 4.90.

3-chloro-4-(p n butyloxybenzyloxy) phenylacetic acid M.P.: 110-111 C. (chloroform-light petroleum):

Calculated (percent): C, 65.41; H, 6.06. Found (percent): C, 65.35; H, 6.05.

3,5-dichloro-4-iso propyloxyphenylacetic acid M.P.: 85-87 C. (cyclohexane):

Calculated (percent) C, 50.10; H, 4.45. Found (percent): C, 50.20; H, 4.59.

3-iso propyloXy-4-propargyloxyphenylacetic acid M.P.: 6769 C. (cyclohexane):

Calculated (percent): C, 72.39; H, 6.94. Found (percent): C, 72.39; H, 6.87.

3-chloro-5-methy1-4-propyloxyphenylacetic acid M.P.: 81-83 C. (light petroleum):

Calculated (percent): C, 59.39; H, 6.23. Found (percent): C, 59.60; H, 6.18.

3-fluoro-4-iso propyloxyphenylacetic acid M.P.: 80.5-81.5 C. (cyclohexane):

Calculated (percent): C, 62.26; H, 6.17. Found (percent): C, 62.13; H, 6.19.

4-allyloxy-3,5-dibromophenylacetic acid M.P.:,106-1065" C. (cyclohexane):

Calculated (percent): C, 37.75; H, 2.88. Found (percent): C, 37.85; H, 2.83.

3-chl0ro-4-propyloxyphenylacetic acid M.P.: 62-63 C. (cyclohexane):

Calculated (percent): C, 57.77; H, 5.73. Found (percent): C, 57.68; H, 5.65.

1 0 3-chloro-4-(AZ-cyclohexenyloxy) phenylacetic acid M.P.: -106 C. (benzene-light petroleum):

Calculated (percent): C, 63.04; H, 5.67; Cl, 13.29. Found (percent): C, 62.96; H, 5.50; Cl, 13.37.

4-sec butyloxy-3-chlorophenylacetic acid M.P.: 72-73 C. (hexane):

Calculated (percent): C, 59.39; H, 6.23. Found (percent): C, 59.28; H, 6.28.

3-bromo-4-propargyloxyphenylacetic acid M.P.: 104105 C. (cyclohexane):

Calculated (percent): C, 49.10; H, 3.37. Found (percent): C, 48.96; H, 3.29.

4-allyloxy-3-brorno-5-chlorophenylacetic acid M.P.: -121 C. (cyclohexane-benzene):

Calculated (percent) C, 43.24; H, 3.30. Found (percent): C, 43.41; H, 3.26.

4-allyloXy-3-cl1loro-5-iodophenylacetic acid M.P.: 109-110 C. (cyclohexane):

Calculated (percent): C, 37.47; H, 2.86. 1 Found (percent): C, 37.49; H, 12.77.

4-iso butyloxy-3-chlorophenylacetic acid M.P.: 79.5-81" C. (light petroleum):

Calculated (percent): C, 59.39; H, 6.23. Found (percent): C, 59.20; H, 6.20.

4-benzyloXy-3-chlorophenylacetic acid M.P.: 120121 C. (ether-light petroleum):

Calculated (percent) C, 65.11; H, 4.74. Found (percent): C, 65.10; H, 4.60.

3-ch1oro-4-n octyloxyphenylacetic acid M.P.: 5858.5 C. (benzene):

Calculated (percent): C, 64.30; H, 7.60. Found (percent): C, 64.40; H, 7.85.

Calculated (percent): C, 62.10; H, 7.20. Found (percent) C, 62.10; H, 7.15.

4-iso amyloxy-3-chlorophenylacetic acid M.P.: 80-81 C. (hexane):

Calculated (percent): C, 60.82; H, 6.67. Found (percent): C, 60.83; H, 6.74.

3-chloro-4-(pdiuorobenzyloxy) phenylacetic acid M.P.: 132- 133 C. (light petroleum-benzene):

Calculated (percent): C, 61.10; H, 4.10. Found (percent): C, 60.97; H, 4.10.

3,5-dichloro-4-n hexyloxyphenylactic acid M.P.: 5858.5 C. (pentane):

Calculated (percent): C, 55.10; H, 5.95. Found (percent): C, 54.92; H, 5.85.

4-iso amyloxy-3,S-dichlorophcnylacetic acid M.P.: 92.593 C. (hexane):

Calculated (percent): C, 53.60; H, 5.55. Found (percent): C, 53.40; H, 5.60.

3-chloro-4-(4'-n buty1oxy-3-cl1lorobenzyloxy) phenylacetic acid M.P.: 133.5-135 C. (benzene):

Calculated (percent): C, 59.54; H, 5.26. Found (percent): C, 59.20; H, 5.20.

4-n amyloxy-3,5-dichlorophenylacetic acid M.P.: 81-81.5 C. (pentane):

Calculated (percent): C, 53.60; H, 5.55. Found (percent): C, 53.30; H, 5.45.

3,5-dichloro-4-n heptyloxyphenylacetic acid M.P.: 59'-59.5 C. (pentane):

Calculated (percent) C, 56.45; H, 6.30. Found (percent) C, 56.60; H, 6.20.

3,5-dichloro-4*n octylphenylacetic acid M.P.: 5253 C. (pentane):

Calculated (percent): C, 57.65; H, 6.65. Found (percent): C, 57.55; H, 6.70.

3-chloro-4- 3'-chloro-4-methoxybenzyloxy) phenylacetic acid M.P.: 145-146 C. (benzene):

Calculated (percent): C, 56.32; H, 4.14. Found (percent): C, 56.45; H, 4.20.

The following examples illustrate the preparation of acids from a substituted nitrile.

EXAMPLE 14 4-ally1oxy-3-chlorophenylacetic acid 103.7 g. of 3-chloro-4-allyloxyphenylacetonitrile in 500 cc. of ethanol, 100 g. of potassium hydroxide and 100 cc. of water are refluxed for 4 hours. Maximum of alcohol is evaporated, the residue is diluted with water and ice, and acidified with 20% HCl. The solid is filtered and washed with petroleum ether. 91.5 g. of acid are obtained (yield: 81%) which is recrystallised from aqueous methanol; melting point: 9293 C.

Analysis.-Calculated (percent): C, 58.29; H, 4.89; Cl, 15.64. Found (percent): C, 58.42; H, 4.93; Cl, 15.55.

EXAMPLE 15 4-allyloxy-3-fluorophenylacetic acid 95 g. of 4-allyloxy-3-fluorophenylacetonitrile (0.5 mol) in 500 cc. of ethanol, 100 g. of potassium hydroxide and 100 cc. of water are refluxed for 4 hours. Maximum of alcohol is evaporated, then one dilutes with water and ice, and the aqueous phase is washed with ether. One acidifies with HQ and the solid is filtered, washed with water and then with petroleum ether. There are obtained 87.2 g. (yield: 83%) of acid which is recrystallised from cyclohexane. M.P.: 77-78.5 C.

Analysis.Calculated (percent): C, 62.85; H, 5.27. Found (percent): C, 62.86; H, 5.25.

EXAMPLE 16 4-crotyloxy-S-methylphenylacetic acid 100.5 g. of 4-crotyloxy-3-methylphenylacetonitrile (0.5 mol) in 500 cc. of ethanol, 100 g. of potassium hydroxide and 100 cc. of Water are refluxed for 4 hours. Maximum of alcohol is evaporated, one dilutes with water and ice, and the aqueous phase is washed with ether, acidified with 20% HCl; the solid is filtered, washed with water and petroleum ether. There are obtained 79.5 g. (yield: 78%) of acid which is recrystallised from petroleum ether; M.P.: 8687.5 C.

Analysis.Calculated (percent): C, 70.88; H, 7.32. Found (percent): C, 70.52; H, 7.28.

EXAMPLE 17 4-n-amyloxy-3-methylphenylacetic acid 103.5 g. of 4-n-amyloxy-3-methylphenylacetonitrile (0.5 mol) in 500 cc. of ethanol, 100 g. of potassium hydroxide and 100 cc. of water are refluxed for 4 hours. Maximum of alcohol is evaporated, the residue is diluted with water and ice, and the aqueous phase is washed with ether, acidified with 20% HCl, and the solid is filtered, washed with water and petroleum ether. There are obtained 85.1 g. (yield: 81%) of acid which is recrystallised from aqueous methanol; M.P.: 134-135 C.

Analysis.Calculated (percent): C, 71.16; H, 8.53. Found (percent): C, 71.02; H, 8.48.

In the same way, the following compounds were prepared.

3-chloro-4-metallyloxyhpenylacetic acid M.P.: 77.5-78.5 C. (petroleum ether-benzene):

Calculated (percent): C, 59.88; H, 5.44. Found (percent): C, 60.08; H, 5.49.

3-chloro-4-propargyloxyphenylacetic acid M.P.: 101-l02 C. (petroleum ether-benzene):

Calculated (percent): C, 58.81; H, 4.04. Found (percent): C, 58.73; H, 3.95.

4-n-amyloxy-3-chlorophenylacetic acid M.P.: 5152 C. (acetic acid-water):

Calculated (percent): C, 60.82; H, 6.67. Found (percent): C, 60.88; H, 6.68.

4-n-butyloxy-3-chlorophenylacetic acid M.P.: 10ll02.5 C. (hexane):

Calculated (percent): C, 59.39; H, 6.23. Found (percent): C, 59.25; H, 6.15.

3-chloro-4-isopropyloxyphenylacetic acid M.P.: 90-92 C. (hexane):

Calculated (percent): C, 57.78; H, 5.73; Found (percent): C, 57.96; H, 5.70.

3-chloro-4-n-propyloxyphenylacetic acid M.P.: 6263 C. (cyclohexane):

Calculated (percent): C, 57.77; H, 5.73. Found (percent): C, 57.68; H, 5.65.

3-fluoro-4propargyloxyphenylacetic acid M.P.: 9395 C. (cyclohexane-benzene):

Calculated (percent): C, 63.45; H, 4.36. Found (percent): C, 63.20; H, 4.29.

4-crotyloxy-3-fluorophenylacetic acid M.P.: 84-86 C. (cyclohexane) Calculated (percent): C, 64.27; H, 5.84. Found (percent): C, 64.55; H, 5.80.

3-fluoro-4'metallyloxyphenylacetic acid M.P.: 82-84 C. (cyclohexane):

Calculated (percent): C, 64.27; H, 5.84. Found (percent): C, 64.31; H, 5.79.

4-n-butyloxy-3-fluorophenylacetic acid M.P.: -86 C. (petroleum ether):

Calculated (percent): C, 63.71; H, 6.63. Found (percent): C, 63.82; H, 6.58.

3-fiuoro-4-n-propyloxyphenylacetic acid M.P.: 99'.5-101 C. (cyclohexane):

:Calculated (percent): C, 62.26; H, 6.17. Found (percent): C, 62.09; H, 6.15.

3-methyl-4-propargyloxyphenylacetic acid M.P.: 94.5-95.5 C. (petroleum ether):

Calculated (percent): C, 70.57; H, 5.92. Found (percent): C, 70.58; H, 5.84.

4-metallyloxy-3-methylphenylacetic acid M.P.: 57-60 C. (methanol-water):

Calculated (percent): C, 70.89; H, 7.32. Found (percent): C, 70.96; H, 7.28.

3-methyl-4-propyloxyphenylacetic acid M.P.: 75-76 C. (hexane):

Calculated (percent): C, 69.21; H, 7.74. Found (percent): C, 68.98; H, 7.72.

13' 4-allyloxy-3-bromophenylacetic acid M.P.: 82-83 C. (cyclohexane):

Calculated (percent): C, 48.73; H, 4.09. Found (percent): C, 48.51; H, 3.92.

14 N-diethylaminoethanol 4-a1ly10xy-3-chlorophenylacetate;

M.P.: 54-56 C. (ether-methanol) Papaverine 4-allyloxy-3-chlorophenylacetate Codeine 4-allyloxy-3-chlorophenylacetate.

With respect to the preparation of alkaline and alkaline- The acids and salts according to the invention are of earth salts of acids according to the invention, this is low toxicity and are useful as pharmaceutic products, madei'ri usual.,way,-'i.e. by treating an acid in alcoholic particularly as anti-inflammatory, analgesic, anti yretic 5 0 o a p solution with. an alcoholic solutn of an alkaline or and ant1spasmod1c agents.

a Hg-$8.11 s t, o owe y evaporation 0 so ven. a1 properties 0 new ac1 s are s own erem er.

thalfll db f 1 t S'd f 'd h h 'aft EMMPLE '18 The values LD of toxicity are given in mg./kg. of body weight on mice, the administration being made per Sodi m alt of 3-611]offl-4-anyloxyphenylace11c acld 0s, the values between brackets giving the 95% confi- .-To-22.6 g. of 3-chIoro-4-allyloxyphenylacetic acid in dance llmlts- 100 cc. of anhydrous methanol, 4 g. of sodium hydroxide The tests lelatlng 0 a ge c power were made by in 200 cc. of anhydrous methanol are added. The meth- Slegmund method [See slegmund' Cadmlel' and anol is then evaporated under vacuum. The residue is G Proc- P 951729 (1957)] and stirred with 100 ccQof-anhydrous ether, filtered and dried by the Randall and Sehtto method [See Archunder vacuum Pharmacodym, III, 409 (19 57)].

in quit-e similar w alkaline and a1kaline earth Salts 20 The Siegmund method g1ves the results for value ED of. various acids according to the invention are prepared, 111 mg/kg Values between brackets glvmg the 95% sothat other examples are not considered as necessary. confidence hmlts- With respect to amine salts of acids,a solution of the T R and Sehtto F glves m terms of 5 acid in anon-polar solvent is treated with the amine the maxlmfllflmcrease of the P threshold desired n The anti-inflammatory activity can be determined by I EXAMPLE 19 the Benitz and Hall method [Arch. Int. Pharmacodyn.,

- g 144:1-2, 185 (1963)] giving the Weight reduction of a a Butylamlm 4-a1ly1OXY-3shlorophenylacetate carrageenin-induced abscess. The anti-inflammatory ac- ,ISO g. of,4-allyloxy-3-chlorophenylac'etic acid are distivity was also determined by the Cotton pellet granuloma so'lvedin 500cc. of anhydrous ether. 50 g. of n-butyltest. We used a mOdlfiCd Me1er test [Mei r R4 Schuler amine are added dropwise while vigorously stirring at d D au les per1ent1a, 6, 469 (1959)]: the room temperature. The precipitate is filtered and Washed treatment by antlphlogistic agents starting three days after ith am -190 g. of'the a ine alt i obt in d; M P the insertion of the pellets. This procedure permits an 98-100? C. (ether-methanol). assessmentof the antiphlogistic power in chronic inflam- 5 matory processes and gives more precise information on EXAMPLE 20 the activity on tissular reaction of the tested compound. Ethanolamine 4-allyloxy-3-chlorophenylacetate The antipyretic activity has been determined by the r following method: Fever is induced in rabbits by i.v.

160 g of 4-allyloxy-3-chlorophenylacet1c acid 31 dls injection of antigonococcal vaccine (200 millions of bacsolved in 500 cc. of anhydrous ether. One equivalent v I. 40 teria per kg.). Otherwise, the technlque is the same as ethanolamme s added dropwise with vigorously stlrrmg.

. that of Baker [Baker J. A., Hayden J., Marshall P. G.,

The salt is filtered. and washed with ether. 173 g. of salt Palmer C. H. R., and W1ttek T. D., I. Pharm. Pharmacol.,

is obtained; M.P.. 733-745 C. (ether-methanol).

I m ame wa the followin Salts are re ared 15, 97T (1963)]. Results are obtained in 10 rabbits for n e 1 g p each compound, the administered dose being always the Triethanolamine 4-allyloxy-3-chlorophenylacetate; same (500 mg./kg.)]. Cross-over design is applied using M.P.: 82-83 C. (ether-methanol) acetylsalicylic acid as reference.

Cyclohexylamine 4-allyloxy-3-chlorophenylacetate; With respect to the antipyretic activity, if one considers ,M.P.: 1333-1345 C. (ether-methanol) that the aspirin has a value of 1, the comparative activity ,B-phenylethylamine 4-allyl0xy-3-chloropl1enylacetate; of 3-chloro-4-allyloxyphenylacetic acid is 4-5 and that of 'M.P.: 101-102" C. (ether-m thanol) 3-methy1-4-allyloxyphenylacetic acid. is 2.

R10- CH-COOH Analgesic activity Antilnfiarnm t atory A u LD1u,mg/kg.,mice, Randallm y pyr tld R1 R: R: R4 per os Siegmund ED Selitto Abcess Granuloma. activity oH,=oH-oH, 01 H H 1,100 $154,485) 25 (17-38) 110-400 0.5 1 5 0H1 -oHCH, 0H:- H H 850 (5564,1101) 140 (05-206) 2 oH,=oH-on, (EH 0 H 'H 2,-250 .1,7a0-2,025) 102 00-158) oH,=oH-oH, o1 CH. H 1, 25 20-1, 1) 30(20-45) 0H,:CH-CH, F H H 1, 900 1, 461-2, 470) 22.5 15-33. 5)

oH,=cH-0H, Br OH; H 1, 050 (1, 422-1, 914) (47-120) CH1=.CHCHI Cl 01 H :975 (757-1, 257) 22.5 (15-33. 8)

cH,- oH-oH, CH1 CH1 H 1, 425 1, 207-1, 681) (45. 7-140) CH;CH=CH-CH| OH; H H .4 400 CH=-CH=CHCH1 Cl H H 73 (51-104) CHg-CH=CH-CH, F H H 2,150 (1,74s-2,045) 98 (445-2150) OH;-CH=CH-OH1 CIHSO H H 825 (1, 351-2, 403) 400 CHEC CH 01 H H 1,025 (sod-1,743) 00 (45-97) 0H- OH: H H 920 752-1,16s) 310 207-405) on: CHzO H 'H 102 (51-204 CH Br on, H 060 (052-1, 411 47 (26-8 CH- F H H 1,125 (8331,519) 22.5 (14.2-35.0)

CHE c1 01 H 840 (072-1, 050) 22 (11. 0-41. 3)

CH5 0H 0 -H H $2,350 102.9 (95. 5-270 01 150-0111 CH: CH, H 1, 425 (1, 168-1, 735) 05 47-9 CHr-CHrCHg 01 H H 1, (947-1, 421) 37 (26-52. 5)

(CHQr-CH 01 H H 1, 400 (1, -1, 750) 138 (70-248 See footnotes at end of table.

TABLEContlnued l l R4 0 H Ra Analgesic activity Antiinflammatory Randall activity Anti- LD o,mg./kg., Siegmund an pyretic R1 R2 R R mice, per os ED5n Selitto 2 Abcess Granuloma activity C1 C1 H H 4, 000 400 CHaO-@-C HP Cl H H i400 c1@cH2- (a) C1 H H 1,600 (1, SSS-1,872) 82 (29-229) 01-- -C H secCrElv C1 C1 H 1, 800 (1, 250-2, 250) 27 (13. 7-53. 2) 1. 2 N C4H9 C1 C1 H 125 (38-406) 1. 2

Cl H H 290 (138-609) 0. CH3- C Hg- Is0C4Hn C1 C1 H i400 3. 2

1 Data are given in mg./kg.; 95% confidence limits. 2 Maximal increase of the giving this maximal increase. 3 Retained for screening.

PHARMACOLO GICAL DATA: STANDARDS 1 Data are given in mgJkg. 95% confidence limits.

2 Maximal increase 01' the pain threshold expressed in grams and observed minutes after treatment; the bracketed values being the mg./ kg. doses giving this maximal increase.

The instant compounds also exhibit a myorelaxant activity:

Antagonism to strychnine lethality Was studied according to R. A. Turner (Screening Methods in Pharmacologyed.: Academic Press, p. 171-1965). The mice were orally or s.c. treated I h. before the iv. injection of strychnine sulfate at a dose of 0.075 trig/kg. The 0.01% strychnine sulfate solution was injected at a rate of 0.02 mL/sec. The animals which survived 30 min. following the injection were considered as protected. Each dose of the drugs was tested in at least 10 animals; control groups were constituted and treated with the excipient alone.

Results for 3-chloro-4-isopropyloxyphenylacetic acid (CP 1044 CG 103) and for the salt of this acid with ethanolamine (CP 1044 CG 103 A).

pain threshold expressed in grams and observed 30 minutes after treatment; the bracketed values being the mgJkg. doses CONCLUSION Orally administered, myorelaxant activity of CP 1044 CG 103 was the same as for mephenesin.

The product administered by so. route had an ED' of 335 mgJkg. and gave a nearly total protection at 600 mg./ kg. in the same test the ethanolarnine salt of 4-allyloxy-3-chlorophenylacetic acid (Mervan) had a ED =800 mg./kg. by so. administration.

Clinical evaluation of analgesic, anti-inflammatory and antipyretic activities of 4-allyloxy-3-chlorophenylacetic acid, 4-allyloxy-3,S-dichlorophenylacetic and 3-chloro- 4-iso-propyloxyphenylacetic acid in man is hereinafter referred to as Mervan, the registered trademark therefor.

/O CHqn-CH-CHgO- 0 -on, o

is hereinafter referred to as CG 90.

CH: O

Kinetic studies of Mervan show a good relationship between analgesic activity and blood levels (see FIG. 1).

(2) Anti-inflammatory activity.--The results for Mervan are provided in Table 2; its activity is comparable to that of phenylbutazone and indomethacin, but the tolerance to Men-van is much better than that to the two reference substances. In double-blind studies, the therapeutic results are expressed according to the opinion of the physician and the preference of the patients.

Concerning the therapeutic activity of CG 103 and CG 90, clinical pilot trials have been undertaken, indicating a very good activity for both compounds: daily doses of 1000 to 3000 mg. CG 103 or 700 mg. CG 90 are used. These trials are performed on patients with rheumatic diseases. Myorelaxant activity of CG 103 seems confirmed in man.

(3) Antipyretic activity.Administered orally or parentally, at the dose of 400 mg., all cases a clearcut drop in temperature.

Its efiicacy in this field was also proven in patients suffering from influenza.

(4) Tolerance-Toxicity.-Generally speaking the tolerance to Mervan, CG 90 and CG 103 is very good; doses up to 6 g./day for Mervan, 3.2 g./day for CG 103 and 1 g./day for CG 90 have been administered for long periods of time. Only a few cases of gastric intolerances and cutaneous rashes have been noted. Body weight, arterial pressure, hematology and blood chemistry were never alfected by the treatments, also renal and hepatic functions are not altered.

As shown in Table 3, acute toxicity of this compound is comparable to that of acetylsalicylic acid, aminopyrine or phenacetine, but much lower than that of codeine, propoxyphene, benzylamine or phenylbutazone.

Chronic toxicity studies 1 were undertaken in rats, monkeys and dogs; the toxicity is particularly weak in the two latter species, in which it was proven that the metabolism of the compound is the most similar to that of man. In the dog, daily doses up to 350 mg./kg. given 10 for three months, seven days a week, do not entail any toxic symptom; in the monkey, in similar conditions, doses up to 250 mg./ kg./ day are perfectly tolerated during one year. Finally, studies in rats, mice and rabbits indicate that Mervan is devoid of teratogenic action.

ACUTE TOXICITY OF MERVAN The analgesic activity of Mervan is investigated in four tests in which the nature and origin of the pain are dif- TABLE 1.ANAL GE SIC ACTIVITY [All double-blind controlled studies] Daily Daily Number of Tested dosage, dosage, patients compound mg. Standard mg. Route Nature of pain Activity 18 Mervan..- 500 Codeine 30 P.o Cancer Mervan significantly supe- T101. 30 Rectal do Comparable for both drugs. P. o. 30 Do. 50 1.111 ..d0 Ratio 1 I160.

0 0 Aspirin 1,000 P.o Post-partum Meriivan significantly supeor. Placebo P.o Neurologic.. CG 103 better than placebo. 20 CG 103..-. 500 Pentazocine 50 R0 ..do Comparable for both drugs and significantly superior to placebo.

TABLE 2.ANTI-INFLAMMATORY ACTIVITY [All comparisons are done according to a double-blind design] Mervan daily Daily Assessment Number of dosage and dosage, patients duration Standard mg. Route Afiection Activity Tolerance 29 1,500 mg., Phenylbutazone 300 R0. Osteoarthritis..." Similar for both drugs Mervan 1 week. better. 47 3,000 mg., Indornethacin 75 P.o. Osteoarthritis and do D 1 month. rheumatoid arthritis. 16 3,000 mg.. No P-o. Rheumatoid In 2/3 of the cases it was Very good.

1 month. arthritis. possible to reduce iteroid administraion. 61 3,000 8-, N0 P 0 -r e\ 1I nat0id Very good results ob- D 7.153 arthritis; 23 tamed in of the days. osteoarthritis. cases.

PHARMACOLOGY OF MERVAN 65 Our studies bearing on arylacetic acids and their derivatives allowed us to select a series of new compounds showing particularly strong analgesic and antipyretic properties; one of them, Mervan, is of great interest for its high potency in these fields and for its low toxicity (I) 75 3 Siegmund,

ferent. In the Siegmund test 3 where the pain is provoked by a chemical stimulus, Mervan appears equivalent to codeine and propoxyphene, twice as active as benzylarnine and glaphenine and three times as active as acetylsalicylic acid (Table 4).

Lambelin 'G., Roba .I., Gillet C., Gautier M. and Buu-Hoi N. P.: Arzn. Forsch. (in the press).

Koster, R., Anderson, M. and De Beer, E. IL: Fed. Proc., 18, 412 (1959).

E., Cadmler, R. and Lu, G.: Proc. Soc. Exp. Biol. N.Y., 95, 729 (1957).

[Drugs administered orally 30 minutes before t]he intraperitoneal injection of acetic acid solution Maximum ED and 0.95 Potency ratio and protection confidence limits Slope 0.95 confidence rate Compound (mg/kg.) S limits percent Mervan 25 (16. 6-38. 5. 34 1 85 (200) Codeine 17 (11. 3-25. 3. 80 3 1. 50 100 (80) Propoxyp 30. 5 (21. 5-43. 3) 2. 67 5 0. 83 85 (100) Pentazocine. 38 (29. 2-49 4) 2. 0 (80) Benzylarnine- 50 5 (35. 3-72 2) 2. 70 0. 50 5 (0. 29-0. 85) 95 (200) Glaphenine 6O (30. 0-120 0) 5. 00 0. 42 5 (0. 19-0. 93) 85 (400) Acetylsalieylic acid- 75 (46. 8-120. 0) 5. 82 0. 33 5 (0. 18-0. 62) 90 (800) Phenacen'ne. 94 (63. 0-141. 3. 38 0. 27 5 (0. 13-0. 55) 85 (400) Aminopyrine. 110 (71-171) 4. 28 0. 23 5 (0. 13-0. 41) 80 (400) Paracetamol..- 180 (120-270) 3. 46 0. 14 5 (0.08-0.25) 80 (400) 1 Mervan considered as unit.

9 Maximum tested dose in mg./kg. in parentheses.

3 Non significantly different; from 1 at the threshold a=0.05. 4 Lack of parallelism.

5 Significantly difierent from 1 at the threshold a=0.05.

In the Randall and Selitto test, pain is induced by pressure on the inflamed paw of the rat. In this test Mervan appears about seven times less active than codeine, it is at least equal to glaphenine and slightly superior to aminopyrine and benzylamine.

In the hot plate test comparison between Mervan, codeine and acetylsalicylic acid is possible; the potency ratio between Mervan and codeine being not significantly different from 1, the two drugs must be considered as equally potent. Both drugs are much more active than acetylsalicylic acid: Mervan is estimated to be fifty seven times as active as this standard. It is well-known that the nonnarcotic analgesics like paracetamol, glaphenine and acetylsalicylic acid are practically devoid of activity in this test. It seems thus that the analgesic activity of Mervan might be quite different than that of the so-called mild analgesics. It was therefore important to investigate the possibility of addiction liability of the drug, but the Straub tail test in mice and investigations in monkeys, physically dependent on 3 mg./kg. morphine, indicate that this hypothesis can be discarded A last test for analgesic activity, using electrical stimulus, the Blake test gives a new comparison of Mervan and codeine. Results show that the intensity of the analgesic activity is comparable for both drugs.

according to a cross-over design, each animal receiving at different moments the drugs to be tested and lactose as a control treatment. It was found that Mervan 200 mg./kg. per os was more active than acetylsalicylic acid 250 mg./kg., and that a subcutaneous administration of 50 mg./kg. Mervan practically inhibited the response to the pyrogen. Typical temperature reduction curves are shown in FIG. 2; they delimit with the zero base line (which represents the temperature under control treatment). Since Mervan reduced temperature by more than 2 C., while acetylsalicylic acid reduced it by only 0.5 C., it is possible to assume that Mervan orally administered is about five times more active than acetylsalicylic acid. On the other hand, it was proven that effective antipyretic doses of Mervan are devoid of hypothermic activity in the normal rabbit.

The anti-inflammatory activity of Mervan was investigated in acute and in chronic inflammatory processes. In the carrageenin-induced oedema of the rat hind-paw, Mervan was compared to phenylbutazone. The results recorded in Table 5 indicate that Mervan is slightly but not significantly superior to the standard. The experiment shows also that the anti-inflammatory activity of our compound is not dependent on the presence of the adrenals.

TABLE 5.CARRAGEENIN INDUCED OEDEMA OF THE RAT HIND PAW Route of R mu. Dose, adminis- Number Norm. or Equation of the Potency Compound mg./kg. tration of rats adren R0 Means ='=S.E. regression line ratio Controls 20 R0. (1) N01'm..... g-

0 i Mervan 40 }P.o. 9 }Norm. 1.76 0. 10 }Y=2.58700.5352X 3 1.11

30 g :15? 8.80 0 1.8 t 6 Phenylbutazone }P o 2 }Norm.....{ *8. }Y=2.46 410.4429 X 1 Controls 0 8.0 10 Norm..... 2.10 0.08 o Mervan ,8 }S.c }Nm-m.-... wig? }Y=2.2746-o.3538X Ihenylbutazone 25 S c 10 Normh." *0'15 Y=2.60650.5033 X 1 100 10 i 1. =0.0fi Controls 0 3.6. J Adron 2.7 0.28 Mervan 100 9 **"1.51 0.09

1 Norm. =normal; Adren. =adrenalcctomized animals.

2 Statistical symbols and are used here to sponding controls; *z significant dill'erence at the 3 Nonsignificantly dillerent from 1.

Finally, reviewing the data on the activity of Mervan, one must point out that its analgesic effective doses do not depress the central nervous system; moreover, tranquilizing and myorelaxant properties do not seem to be involved in the analgesic action of the drug.

The antipyretic activity of Mervan was studied in rabbits rendered hyperthermic by intravenous injections of antigonococcic vaccine. The experiments were conducted 4 Randall, L. O. and Selitto, J. J. Arch. Int. Pharmacodyn, .111. 409 (1957).

Eddy, N. 13., and Leimhach, 0.: J. Pharmacol. Exp. The): 107. 385 (1953).

May, E. L.: Personal Communication (1969).

7 Blake, L., Graeme, M. L. and Sigg, E. B. Med. Exp. 9, 146 (1963).

1' the comparison of the means of treated animals with those of the correthreshold 01:0.05, 0.01, 0.001 respectively.

Winter, C. A., Risley, E. A. and Nnss, G. W.: Proo. Soc. Ext). Biol. Med.., 111, 544 (1962).

9 Glenn, E. M. and Gray, J. Am. .1. Vet. Res, 26, 114, 1180 (1905).

Glenn, E. M. Am. J. Vet. Res, 27, 116, 339 (1966).

24 a warm solution of gelatine 20 l. and about l. of cold water C.).

The resulting damp granules were passed through a No. 4 mesh screen (aperture size 5.13 mm); trayed and dried at 50 C. for about 16 hours in an oven.

TABLE 6.-ADJUVANT-1NDUCED POLYAR'IHRlTlS IN THE RAT: PREVENTIVE TREATMENT (20 ANlMALS/DOSE).

Incidence 1 Daily Route of Scores: n1eans* S.E. Body weight doses, adminis- On On gain Means Mor- Cornpound rug/kg. tration On day 15 On day 21 day 15 day 21 *S.E., g. tality Controls 0 P.0. 5.17 *1. 19 6. 41 *1. 53 14/18 12/17 -7. 00 *7. 89 3 Me 5} P O {"0. 72 *0. 50 0. 94 *0. 40 *2/18 *6/18 2 6. 87+ 2. 00* 2 2 mm 10o :0. 60 *0. "0. e3 *0. 40 "5/15 5/15* 1 +2.08 *5.18 z 5 25 2. 25 *1. 02 *3. 00 *1. 13 *6/16 2 8/15 2 2. 53 *6. 76 2 5 Phenylbutamn" 100} i**0. 29 0. 22 "0. 33 i0. 34 "*2 14 2 6/12 2 10. 69 5. 22 2 s 0 8.0. 5. 10 *0. 94: G. *1.15 18/20 18/20 11. 50 *8. 00 0 25} S c {"2. 15 *0. 74 **2. 10 *0. 55 *8/20 11/20 2 +1. 20 *8. 50 0 lg? 65 *0. 27 *0. 66 *5/20 *6/20 -I-"*19. 20 *7. 80 0 1. 80 *0. 61 2. 40 *0. 70 9/20 *12 20 "17. 60 *7. 50 0 Phenylbutazon" 100i i**0. :0. 22 "1. 35 =0. 42 "*5 20 "9420 +*14 is. 30 0 1 Incidence: number of animals presenting arthritic lesions.

2 Nonsigniiicantly difierent from the corresponding controls at the threshold a=0. "*z significantly difierent from the corresponding controls at the threshhold 05. a=0.05, 0.01, 0.001 respectively.

The dried granulation was then passed through a No. 8 mesh screen (aperture size 1.95 mm.) and a No. 14 mesh screen (aperture size 1.25 mm.).

After being thoroughly mixed with corn starch and aerosil composition, the granulated material was compressed into tablets weighting 650 mg. each.

Punch diameter: 13 mm.

Average Weight: 650 mg.

Hardness: 10-15 kg. stokes.

Disintegration time-before 10 min.

Friabilitynot more than 0.5%.

TABLE 7.ADJUVANT-INDUCED POLYARTHRITIS IN THE RAT: CURATIVE TREATMENT Scores (Means*S.E.)

Daily Numdose, ber Day 14 Bodyweight mg./ of (before gain, g. means Compound kg. rats treatment) Day 17 Day 19 Day 21 Day 24 Day 26 Day 28 *SJE.

Controls. 0 17 5.18 *1. 02 6. 47 =+=1. 07 7.06 *0. 98 7. 71 *1. 06 7. 47 =*=1. 18 7. 76 *1. 18 7. 58 i=1. 15 9.18 *6. 30 Mervan.-- 100 13 5. 53 *1. 21 1. 02 *1. 02 *3. 61 *0. 67 4. 92 *1. 06 *4. 31 *0. 02 *4. 15 *0. 93 3. 53 *0. 65 l 10. 15 *5. 1 Phcnylbutazone 13 5.85 =1. 24 5. 46 *1. 10 *3. 60 *0. 84 *3. 54 *0. 75 *3. 08 =0. 64 2. 61 =0. 50 2. 46 :|:0. 53 1 1 1. 62 =5. 07

1 Nonsignificantly different from the controls at the threshold 11 005. Significantly dillcrent from the controls at the threshold a=0.05. Significantly different from the controls at the threshold 0: =0.01.

tablet, mg.

For a batch of 200,000

The basic formulation is tablets, Kg.

4-allyloxy-S-chlorophenyl acetic acid (Mervan) Prejel (a starch soluble binder) Gelatine G1ycerin Corn starch Acrosil composition (diatomite used as glider) The Mervan and prejel were thoroughly mixed and passed through a comminuting mill to insure uniformity.

A 10% gelatine was made by dissolving in warm water with glycerin (201).

The mixture of prejel and Mervan was granulated with MANUFACTURE OF ME RVAN INJECTABLE LIQUID For 1 For a batch ampoule, of 10,000 The basic formulation is mg. ampoules kg.

4-allyloxy-3-ch1orophcnylacetic acid (Mervan) 393. 75 3. 937 Monocthanol amine 10G. 25 1. 0,62 Xylocaine hydroch1oride 30 0. 300 Benzyl alcohol 45 0. 450 Sodium metabisulfite. 8 0. 030 Water for injection ad 3 2 30 1 Milliliter. 2 Liter.

In a 50 l. balloon flask equipped with a stirrer, the monoethanolamine, benzyl alcohol and sodium metasulfite were dissolved in 20 1. water for injection (oxygen free) while nitrogen was continuously bubbled through the solution. The Mervan was dissolved in this solution while stirring was effected. After the Mervan entirely dissolved Xylocaine was dissolved thereinto. The resultant solution was diluted with water for injection (oxygen free) to volume.

The solution was then filtered through a 0.22 microns millipore filter under nitrogen pressure and sterilized brown ampoules were filled therewith under nitrogen protection.

Mervan suppositories:

Formula: Witepsol H15 (lauric acid, 1400 mg., 5

glyceric ester used as base for suppositories); Mervan, 600 mg. Method of manufacture:

Melt the Witepsol H15, add the Mervan and mix using an ultra Turax type mixer. Pour into mold.

As an example of use of ethanolamine salt of 3-chloro- 4-allyloxyphenylacetic acid as liquid for injection, the composition is as follows:

Salt 1 0.166

Xylocaine 0.010

Benzyl alcohol 0.015

We claim:

1. 3-chloro-4-ally1oxyphenylacetic acid.

26 References Cited UNITED STATES PATENTS 3,385,886 5/1968 Nicholson et al. 280521 R 3,586,713 6/1971 Boo-Hoi et al. 260-473 R FOREIGN PATENTS 901,614 8/1945 France.

US. Cl. X.R.

. UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,824,277 Dated July 16, 1974 Inventofls) NGUYEN PHUC BUU-HOI et :11

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 11, change. "1974 to --l967--.

Column 26, line 4, change "Boo" to --Buu--.

Column 26 line 10, change "Boo" to -Buu--.

Signedand sealed this 19th day of November 197% (SEAL) Attest:

MCCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents USCDMM-DC 60376-P69 FORM PO-1050 (10-69) us. GOVERNMENT PRINTING OFFICE: ISIS 0-366-334- 

